ELABELA ameliorates hypoxic/ischemic-induced bone mesenchymal stem cell apoptosis via alleviation of mitochondrial dysfunction and activation of PI3K/AKT and ERK1/2 pathways

Abstract

Background Mesenchymal stem cells (MSCs) have exerted their brilliant potential to promote heart repair following myocardial infarction. However, low survival rate of MSCs after transplantation due to harsh conditions with hypoxic and ischemic stress limits their therapeutic efficiency in treating cardiac dysfunction. ELABELA (ELA) serves as a peptide hormone which has been proved to facilitate cell growth, survival, and pluripotency in human embryonic stem cells. Although ELA works as an endogenous ligand of a G protein-coupled receptor APJ (Apelin receptor, APLNR), whether APJ is an essential signal for the function of ELA remains elusive. The effect of ELA on apoptosis of MSCs is still vague. Objective We studied the role of ELABELA (ELA) treatment on the anti-apoptosis of MSCs in hypoxic/ischemic (H/I) conditions which mimic the impaired myocardial microenvironment and explored the possible mechanisms in vitro. Methods MSCs were obtained from donated rats weighing between 80~120 g. MSCs were exposed to serum-free and hypoxic (1% O2) environments for 24 h, which mimics hypoxic/ischemic damage in vivo, using serum-containing normoxic conditions (20% O2) as a negative control. MSCs that were exposed to H/I injury with ELA processing were treated by 5 μM of ELA. Cell viability and apoptosis of MSCs were evaluated by CCK8 and flow cytometry, respectively. Mitochondrial function of MSCs was also assessed according to mitochondrial membrane potential (MMP) and ATP content. The protein expression of key kinases of the PI3K/AKT and ERK1/2 signaling pathways involving t-AKT, p-AKT, t-ERK1/2, and p-ERK1/2, as well as apoptosis-related protein expression of Bcl-2, Bax, and cleaved Caspase 3, were monitored by Western blot. Results We found that ELA treatment of H/I-induced MSCs improved overall cell viability, enhanced Bcl/Bax expression, and decreased Caspase 3 activity. ELA inhibited H/I-induced mitochondrial dysfunction by increasing ATP concentration and suppressing the loss of mitochondrial transmembrane potential. However, this anti-apoptotic property of ELA was restrained in APJ-silenced MSCs. Additionally, ELA treatment induced the phosphorylation of AKT and ERK, while the blockade of PI3K/AKT and ERK1/2 pathways with respective inhibitors, LY294002 and U0126, suppressed the action of ELA. Conclusion ELA positively affected on the survival of MSCs and exhibited anti-apoptotic characteristics when exposed to hypoxic/ischemic condition in vitro. Also, the function of ELA was correlated with the APJ receptor, reduced mitochondrial damage, and activation of the PI3K/AKT and ERK1/2 signal axes.

Endometrial stem/progenitor cells and their roles in immunity, clinical application, and endometriosis

“…Co-culture of endometrial cells (epithelial or stromal) derived from menstruation with CD140b + CD146 + eMSCs enhances the cloning and self-renewal activities of CD140b + CD146 + eMSCs. Co-culture of CD140b + CD146 + cells with the endometrial niche cell conditioned media containing the high levels of interleukin 6, C-X-C motif ligand 1 (CXCL1) and CXCL5 may increase the proliferation and self-renewal abilities of CD140b + CD146 + eMSCs [ 17 ].

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“…Most importantly, any significant side effects including acute, subchronic, or chronic poisoning, infection, tumorigenesis, or endometriosis has not been reported either in preclinical studies or in clinical studies during the treatments of various diseases with MenSCs over the past yeas [ 54 – 56 ] (Table 2 ). Existing studies have found that MenSCs therapy may be an attractive alternative approach for intrauterine adhesion (IUA) [ 57 ], premature ovarian failure (POF) [ 58 , 59 ], liver failure [ 60 – 62 ], experimental stroke [ 63 ], pulmonary fibrosis [ 64 , 65 ], cardiac diseases [ 66 , 67 ], myocardial infarction [ 46 , 68 ], Alzheimer’s disease [ 69 ], acute lung injury [ 70 ], acute respiratory distress syndrome [ 71 ], renal ischemia reperfusion injury [ 72 ], sciatic nerve injury [ 73 ], chronic nonhealing wounds [ 74 ], and type 1 diabetes [ 75 ] (Table 2 ).…”

“…Existing studies have found that MenSCs therapy may be an attractive alternative approach for intrauterine adhesion (IUA) [ 57 ], premature ovarian failure (POF) [ 58 , 59 ], liver failure [ 60 – 62 ], experimental stroke [ 63 ], pulmonary fibrosis [ 64 , 65 ], cardiac diseases [ 66 , 67 ], myocardial infarction [ 46 , 68 ], Alzheimer’s disease [ 69 ], acute lung injury [ 70 ], acute respiratory distress syndrome [ 71 ], renal ischemia reperfusion injury [ 72 ], sciatic nerve injury [ 73 ], chronic nonhealing wounds [ 74 ], and type 1 diabetes [ 75 ] (Table 2 ).…”

Peptide hormone ELABELA promotes rat bone marrow-derived mesenchymal stem cell proliferation and migration by manipulating the cell cycle through the PI3K/AKT pathway under the hypoxia and ischemia microenvironment

“…RAT BM-MSCs were obtained from SD rats by flushing femurs and tibias as previously described [ 13 , 20 ]. The isolated RAT BM-MSCs were cultured in the complete culture medium which was composed of low-glucose Dulbecco modified eagle medium (GIBCO), 10% fetal bovine serum (GIBCO), penicillin (100 IU/ml) and streptomycin (100 μg/ml) (HyClone).…”

“…The ELA-APJ axis is a promising therapeutic target for cardiovascular diseases [ 11 , 12 ]. Intriguingly, our previous study found that ELA could alleviate the apoptotic level of MSCs via the PI3K/AKT and ERK1/2 signaling pathways under hypoxic and ischemic conditions [ 13 ]. The PI3K/AKT signaling pathway is known to play a central role in modulating cellular processes of MSCs involving cell proliferation, migration, and apoptosis [ 14 , 15 ].…”